oecd qsar toolbox v.3 · 2016-03-29 · structure assigned to the target chemical is the correct...

OECD QSAR Toolbox v.3.3

Example for predicting Skin Sensitization of mixture with known components

Outlook

23.02.2015 The OECD QSAR Toolbox for Grouping Chemicals into Categories 2

• Background

• Objectives

• The exercise

• Workflow

• Save the prediction

Background

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• This is a step-by-step presentation designed to take the user of the Toolbox through the workflow for prediction skin sensitization of mixture with known components

The OECD QSAR Toolbox for Grouping Chemicals into Categories 23.02.2015

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Outlook

• Background

• Objectives

• The exercise

• Workflow



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Objectives

• This presentation reviews a number of functionalities of the Toolbox:

• 2D editor for defining Mixture components

• Filling data gaps by Independent mode approach


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Outlook

• Background

• Objectives

• The exercise

• Workflow



• In this exercise we will predict the skin sensitization of mixture, which is the “target” chemical.

• Investigate the mode of action for each components of the mixture

• Gather available experimental data for target chemical

• Investigate skin sensitization of non-tested component

• Applying read across for non-tested component

• Predict skin sensitization potential of mixture based on experimental data of tested compounds and predicted data of non-tested one.

Exercise

7 The OECD QSAR Toolbox for Grouping Chemicals into Categories 23.02.2015

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Outlook

• Background

• Objectives

• The exercise

• Workflow



• The Toolbox has six modules which are used in a sequential workflow:

• Chemical Input

• Profiling

• Endpoints

• Category Definition

• Filling Data Gaps

• Report

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Workflow


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Outlook

• Background

• Objectives

• The exercise

• Workflow

• Input


• This module provides the user with several means of entering the chemical of interest or the target chemical.

• Since all subsequent functions are based on chemical structure, the goal here is to make sure the molecular structure assigned to the target chemical is the correct one.

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Chemical Input Overview


User alternatives for defining mixtures with known compositions:

• Chemical Name

• Chemical Abstract Services (CAS) number (#)

• SMILES (simplified molecular information line entry system) notation/InChi

• Drawing mixture constituents and defining their quantities

• Select from User List/Inventory/Databases

• Chemical IDs such as EC number, Einecs number

• Load file with mixture

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Chemical Input Ways of Entering a mixture


• Open the Toolbox.

• The six modules in the workflow are seen listed next to “QSAR TOOLBOX”.

• Click on “Input” (see next screen shot)

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Getting Started


Chemical Input Input Screen

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• Toolbox allows to enter target chemicals through tab delimited file

• This requires mixture with defined components to be previously defined in a tab delimited file

• The subsequent series of screen shots will take you through the process of entering the target chemical via tab delimited file

• In this particular case, the example file with mixture is available in the Example directory of Toolbox installation (C:\Program Files (x86)\QSAR Toolbox\QSAR Toolbox 3\Examples)

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Chemical input Load list with chemical mixture


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1. Click on Chemical list 2. Browse and find the file with mixture located at Examples directory 3. Select the file 4. Open the file “Mixture with defined quantities.smi”



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The notification message appears, informing the user that there are structures without CAS numbers. If you want the software to search databases for their CAS numbers, click Yes, otherwise click No. 1. Select No



• The already drawn target structure automatically appears on the data matrix

• Note that no CAS number or name is displayed for this chemical. This means the target chemical is not listed in the chemical inventories/databases available in Toolbox(see next slide).

• Visualization of components of the mixture is possible when user selects Single Component Mode

Chemical Input Target chemical identity



1. Select “[set][Mix]{X=1/Miligrams…..}” of mixture 2. Component Mode functionality appears. All components

mode is selected by default (3)

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“Single” component mode visualize all components of the mixture and allows the user to work with each of the components as individual substance (1)

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Outlook

• Background

• Objectives

• The exercise

• Workflow

• Input

• Profiling


• “Profiling” refers to the electronic process of retrieving relevant information on the target compound, other than environmental fate, ecotoxicity and toxicity data, which are stored in the Toolbox database.

• Available information includes likely mechanism(s) of action, as well as observed or simulated metabolites.

Profiling Overview


• For most of the profilers, background information can be retrieved by highlighting one of the profilers (for example, Protein binding by OASIS v1.3 and clicking on “View’’ (see next screen shot).

Profiling Side-Bar to Profiling


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23.02.2015 The OECD QSAR Toolbox for Grouping Chemicals into Categories

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Domain

Mechanistic

alert

Structural

alert

List with categories Textual description

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1. Highlight the profiler 2. Click View 3. Click Advance in order to see detailed description of highlighted category (in this case “Aldehydes”)

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1. Highlight the profiler 2. Click View 3. Select “Aldehydes”

Structural boundaries

Structural fragment

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• Select the “Profiling methods” related to the target endpoint by clicking on the box next to the profilers name.

• This selects (a green check mark appears) or deselects (green check disappears) profilers.

• For this example, select the following profilers relevant to the Skin sensitization (see next screenshot):

- Protein binding by OASIS v1.3 – general mechanistic

- Protein binding by OECD – general mechanistic

- Protein binding potency – general mechanistic

- Protein binding alerts for skin sensitization by OASIS v1.3 –

endpoint specific

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Profiling

Profiling the target chemical


1. Check the profilers related to the target endpoint; 2. Click Apply.

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This component has positive protein binding alert



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Outlook

• Background

• Objectives

• The exercise

• Workflow

• Input

• Profiling

• Endpoint


• “Endpoint” refer to the electronic process of retrieving the environmental fate, ecotoxicity and toxicity data that are stored in the Toolbox database.

• Data gathering can be executed in a global fashion (i.e., collecting all data of all endpoints) or on a more narrowly defined basis (e.g., collecting data for a single or limited number of endpoints).

• In this example, we limit our data gathering to the common Skin endpoints from databases containing Skin Sensitization data

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Endpoint


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1. Select databases related to the target endpoint by adding a green check in the box before the database name.

2. Click Gather

Endpoint

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Endpoint Process of collecting data

In this example, negative skin sensitization experimental data have been found for the two

components


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Recap

• You have entered the mixture with defined components

• You have profiled the target chemical mixture and found no protein binding alerts for two of the mixture constituents. The third constituent has positive protein binding alerts and could elicit skin sensitization effect

• Negative experimental data has been found for two of mixture components. No experimental data has been found for the third constituent

• The constituent without experimental data and positive protein binding alert has been used for further read across analysis. Then, all of the available data –

experimental and predicted will be used for SS prediction of the mixture.

• Now you are ready to continue with “Read across prediction of constituent without data”.


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Outlook

• Background

• Objectives

• The exercise

• Workflow

• Input

• Profiling

• Endpoint

• Read across prediction of constituent without data

• Focus constituent without experimental data


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1. Right click over the chemical without experimental data 2. Select Focus

This consituent is selected for further read-across prediction

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Read across prediction of constituent without data Focus constituent


This focused component appeared in separate data matrix

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Read across prediction of constituent without data Focus constituent


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Outlook

The OECD QSAR Toolbox for Grouping Chemicals into Categories

• Background

• Objectives

• The exercise

• Workflow

• Input

• Profiling

• Endpoint



• Define category

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• This module provides the user with several means of grouping chemicals into a toxicologically meaningful category that includes the target molecule.

• This is the critical step in the workflow.

• Several options are available in the Toolbox to assist the user in refining the category definition.

Category Definition Overview


• The different grouping methods allow the user to group chemicals into chemical categories according to different measures of “similarity”.

• Detailed information about grouping chemical (Chapter 4) could be found in document “Manual for Getting started” published on OECD website:

http://www.oecd.org/chemicalsafety/risk-assessment/theoecdqsartoolbox.htm

Category Definition Grouping methods





Basic guidance for category formation and assessment

Suitable categorization phases:

1. Structure-related profilers 2. Endpoint specific profilers (for sub-cat) 3. Additional structure-related profilers, if needed to eliminate dissimilar

chemicals (to increase the consistency of category) (e.g. chemical elements)

Performing categorization:

1. The categorization phases should be applied successively 2. The application order of the phases depend on the specificity of the data

gap filling 3. More categories of same Phase could be used in forming categories 4. Some of the phases could be skipped if consistency of category members is

reached Graphical illustration of suitable categorization phases is shown on next slide


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Metabolism accounted for

Phase II. Mechanism based

• DNA binding mechanism

• Protein binding mechanism

• Genotoxicity/carcinogenicity

• Cramer rules

• Verhaar rule

• Skin/eye irritation corrosion rules

• US EPA Categorization

• OECD Categorization

• Organic functional group

• Structural similarity

• ECOSAR

Phase I. Structure based

Repeating Phase I due to Multifunctionality of chemicals

Broad grouping

Endpoint Non-specific

Subcategorization

Endpoint Specific

Subcategorization

Endpoint Specific

Phase III. Eliminating dissimilar chemicals

Apply Phase I – for structural dissimilarity

Filter by test conditions – for Biological dissimilarity

Suitable Categorization/Assessment Phases

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• US EPA Categorization

• OECD Categorization

• Organic functional group

• Structural similarity

• ECOSAR

Phase I. Structure based

Repeating Phase I due to Multifunctionality

of chemicals

Broad grouping Endpoint Non-specific

Suitable Categorization/Assessment Phases

Read across prediction of constituent without data Forming category for studied endpoint

Phase I categorization in Toolbox

It is not recommended to use “Neutral organic” * as phase I

*Neutral organic category include chemicals having different functionalities as alcohols, ketones, ethers etc. In this respect the basic principle that structurally similar chemicals may elicit similar effects would not be preserved, because Neutral organic mixed many different functionalities

46 analogues are identified as Aryl halides by OFG

• Based on the above recommendations and classifications from structurally similar profilers the OFG is used as initial categorization group

• Refinement of the initial group is based on endpoint-specific protein binding profiler:

• Protein binding alerts for skin sensitization by OASIS v1.3.

See next slides

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Read across prediction of constituent without data Forming category for studied endpoint

Category definition is a tool for grouping chemicals, which allows to group chemicals based on different measures of “similarity”. For more details see tutorials posted on LMC and OECD website:

http://www.oecd.org/env/ehs/risk-assessment/theoecdqsartoolbox.htm

http://superhosting.oasis-lmc.org/products/software/toolbox/toolbox-support.aspx










1. Select OFG 2. Click Define Combination of three organic functional groups identified a single analogue (3). In order to expand the category Aryl halide is used only. See next slide

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Based on above recommendations the OFG is used as an initial group (phase I)

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Read across prediction of constituent without data Define category by OFG

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1. Select OFG 2. Click Define 3. Select Aryl and Ketone and remove 4. Click arrow down 5. Aryl halide should be remained only 6. Click OK

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Except Aryl halide all other groups are removed by selecting the categories

and clicking on arrow down

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Read across prediction of constituent without data Define category by OFG

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Outlook

• Background

• Objectives

• The exercise

• Workflow

• Input

• Profiling

• Endpoint



• Define category

• Gather data for analogues


1. Click OK 2. Click OK in order to read data for all endpoints

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Read across prediction of constituent without data Gather data for analogues chemicals

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The experimental data for the identified analogues appears on data matrix

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Read across prediction of constituent without data Gather data for analogues chemicals


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Outlook


• Background

• Objectives

• The exercise

• Workflow

• Input

• Profiling

• Endpoint



• Define category

• Gather data for analogues

• Apply read across 23.02.2015

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Assays and Endpoints are mixed

1. Click on the cell corresponding to Skin Sensitization in Vivo 2. Select Read-across 3. Click Apply 4. Click OK (in this case we mixed all endpoints and assays)

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Read across prediction of constituent without data Apply read across

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Read across prediction of constituent without data Subcategorization

• The initial category could be refine by subcategorizing the analogues according to the following endpoint specific profiler (phase II, slide #37):

- Protein binding alerts for skin sensitization by OASIS v1.3.

• These steps are summarized in the next screen shots.


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Read across prediction of constituent without data Subcategorization by Protein binding alert for SS

1. Select filter data/subcategorize 2. Select Protein binding alerts for SS by OASIS v1.3. 3. Click Remove to eliminate dissimilar chemicals.

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Almost all analogs have been found to be positive. Predicted SS effect of

the target is positive

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1. Click Accept prediction 2. Click OK 3. Return to matrix

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Outlook

• Background

• Objectives

• The exercise

• Workflow

• Input

• Profiling

• Endpoint


• Filling data gap for skin sensitization of mixture


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Filling data gap for skin sensitization of mixture Applying Independent Mode of Action

Here is the Read across prediction for Skin sensitization of the constituent without data

Here are the experimental data for

Skin sensitization

Next step: Applying Read across for the mixture


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1. Click on the cell corresponding to Skin Sensitization for mixture 3. Click Apply 2. Select Independent MOA 4. Click OK

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Read across is applied for the mixture (assuming Independent Mode of Action) “Maximal” approximation type is set by default for categorical endpoints (worst case scenario)(see 1)

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1. Accept prediction 2. Return to matrix

Based on the positive skin sensitization value for one of the mixture components the prediction for the mixture is positive

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Read across prediction for the mixture based

on predicted and experimental data of mixture

constituents appears on datamatrix

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Outlook

23.02.2015

• Background

• Objectives

• The exercise

• Workflow

• Input

• Profiling

• Endpoint


• Filling data gap for skin sensitization of mixture

• Generating report for mixture


Report

• Remember the report module allows you to generate a report on the predictions performed with the Toolbox. This module contains predefined report templates as well as a template editor with which users can define their own user defined templates. The report can then be printed or saved in different formats.

• Generating the report is shown on next screenshots


Report

1. Select prediction 2. Right Click and Select Report

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Report

Toolbox report for mixture


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1. Summary information for mixture prediction

Report


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Outlook

23.02.2015

• Background

• Objectives

• The exercise

• Workflow

• Save the prediction result


Saving the prediction result

67 The OECD QSAR Toolbox for Grouping Chemicals into Categories

• This functionality allow storing/restoring the current state of Toolbox documents including loaded chemicals, experimental data, profiles, predictions etc, on the same computer. The functionality is implemented based on saving the sequence of actions that led to the current state of the Toolbox document and later executing these actions in the same sequence in order to get the same result(s).

• Saving/Loading the file with TB prediction is shown on next screenshots

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Saving the prediction result


1. Go to Input section 2.Click on Save button 3. Define name of the file; 4. Click Save button

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Open saved file


1. Create new document 2. Click Open; 3. Find and select file; 4. Click Open

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Open saved file


1. The file is opened successfully 1. Click OK

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oecd qsar toolbox v.3 · 2016-03-29 · structure assigned to the target chemical is the correct...

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